Morphine is the prototype of the class of opioid analgesic drugs which exert their effects by activating opioid receptors within the brain. When morphine is referred to individually in this application, this reference is meant to encompass other opioid drugs and is not meant to be morphine exclusively. Historically, narcotics have been used since the 18th century in the forms of oral or injectable morphine or opium in order to accomplish pain relief. Morphine is considered to be unsurpassed as an analgesic for severe pain.
Unfortunately, morphine and other opioid drugs have a number of severe side effects which hamper their wide spread use and acceptance by both physicians and patients. These side effects include: addiction, nausea, inhibition of breathing, somnolence and dysphoria, all of which are mediated by morphine's action within the brain. It is still the current belief that narcotics ingested or injected will cross to the blood stream and from there go to the brain where there are morphine receptors. At that time, the narcotics are believed to attach to these morphine receptors and create a dullness of the pain but with all of the side effects described above. Of course, the worst potential effect is the addiction that can occur if the morphine is used beyond a few days or weeks on a continuous basis.
Because of the fear of addiction, the use of morphine as an analgesic has been restricted. In addition, major research efforts have been directed toward the development of morphine-like drugs that act within the brain but are devoid of the side effects. The market for these other drugs has never fully materialized because these drugs were not perceived as having the same analgesic properties of morphine and because typically these drugs were not produced to be both available in oral and injectable formats.
In the past ten years, the intraspinal method of treating pain has been extensively developed but, as more extensive use was made of this technique, a number of serious problems developed. The first problem is that the intraspinal method of treatment requires a spinal tap which of course necessitates the use of a needle to the spinal cord. The second problem results from the first in that if it is necessary to use the intraspinal method over a period of time, such as two or three weeks, medication must be injected into the spine for this period of time and the continuous needle sticks into the spine has potential hazards. Further, if it is necessary to use the intraspinal method over time, even though the dosage is substantially less compared to oral or intravenous dosages, there is still a high potential for addiction and with such addiction the resultant problems of withdrawal and its associated side effects.
Although intraspinal application of narcotics is still used to alleviate pain after surgery, this technique has the limitations with the potential for addiction as described above. In addition, it has been determined that with frail patients there is the risk that the patient can stop breathing and there have been a number of cases of respiratory arrest after the administration of narcotics using the intraspinal technique. Further, the intraspinal technique of administering narcotics creates difficulty with male patients and especially with elderly male patients in that there can be problems with urination and with consequent problems of urine retention. Finally, this intraspinal technique produces a significant itching problem as a side effect.
In more recent studies it was discovered that opioid receptors may also be located in other peripheral tissues. This was reported in Stein, C. et al., Peripheral effect of fentanyl upon nociception in inflamed tissue of the rat. Neurosci. Lett. 84:225-228 (1988), and in Stein, C. et al., Antinociceptive effects of mu- and kappa-agonists in inflammation are enhanced by a peripheral opioid receptor-specific mechanism of action. Eur. J. Pharmacol. 155:255-264 (1988). Subsequently, animal experiments were performed in Dr. Stein's laboratory characterizing peripheral opioid receptors and their activation by morphine and other opioid drugs. This was reviewed in Stein, C., Peripheral mechanisms of opioid analgesia. Anesth. Analg. 76:182-191 (1993), and in Stein, C., Lehrgerger, K., Yassouridis, A., Khoury, G.: Opioids as novel intraarticular agents in arthritis. In: Progress in Pain Research and Management, Fields, H. L., Liebeskind, J. C., eds., 1:289-296, IASP Press, Seattle, (1994). A most important determination from these various studies is that the doses of the drugs required to produce analgesia in the peripheral tissues are extremely small and therefore devoid of the above mentioned side effects produced by dosages sufficient to operate on the brain.
In addition, it was determined that the endogenous ligands of peripheral opioid receptors (endorphins, the body's own pain killers) are located within the inflamed tissue. It was also determined that the endorphins can produce intrinsic analgesia within peripheral tissues both in animals and in humans (Stein (1993), ibid.). It was further noted that the peripheral opioid effects were more pronounced in inflamed than in non-inflamed tissues.
An anecdotal preliminary study reported an attempt to transdermally locally administer 1-3 mg of morphine to the backs of patients who had undergone failed back operations, primarily using mechanical methods of enhancing skin penetration and absorption of the morphine (ultrasound, massage, heat) as well as by the use of the occlusive topical vehicle Aquaphor (F. Tennant et al., Topical morphine for peripheral pain. Lancet 342:1047-1048 (1993)). Some improvement in pain relief was noted, and the authors speculated that it was due to binding of the morphine to peripheral opioid receptors in inflamed (presumably myofascial) tissue directly under the skin to which the morphine was applied, and absence of morphine in the systemic circulation was claimed. This result is scientifically questionable, however, based on the data of the present invention: there had to be sufficient transdermal transport to carry the morphine completely through the skin and into the underlying inflamed myofascial tissues, which would almost certainly result in a detectible amount of morphine being carried in the systemic circulation. Alternatively, it is possible that the pain relief noted was not reproducible. It is notable that no further reports of this type of administration have been reported since, either by that group or any others.
None of these reports discussed the possibility that pain relief could be topically induced in skin, whether inflamed or not, nor was it even known whether peripheral opioid receptors are present in human skin.
Severe pain caused or accompanied by inflammation in skin is a particularly intractable problem, because the underlying reasons for it tend to be both long-term and yet not inherently life-threatening, e.g., shingles and various kinds of burns, both of militate against the chronic systemic use of opioid agents. This led to initial investigations into whether it might be possible to be able to induce effective opioid analgesia in such cases without the negative effects of systemic opioid administration. U.S. Pat. No. 5,589,480, ElKhoury and Stein, discloses the use of topical opioid analgesics in inflamed skin or mucosal tissue, whereby effective analgesia in the inflamed skin or mucosal tissue is induced in the substantial absence of transdermal or transmucosal delivery of the opioid analgesic agent. As with any such application, improvements in the effectiveness of the methods and preparations, e.g., in the effectiveness of analgesia thus induced, would be desirable.
However, as noted above, peripheral opioid effects are more pronounced in inflamed than in non-inflamed tissues. There still remains the problem of severe pain in intact skin unaccompanied by inflammation, which also is an intractable problem, again, because the underlying reasons for it tend to be both long-term and yet not inherently life-threatening, e.g., diabetic peripheral neuropathy and postherpetic neuralgia, both of which militate against the chronic systemic use of opioid agents. Therefore, it would be a great benefit to be able to induce effective opioid analgesia in such cases without the negative effects of systemic opioid administration.